TY - JOUR
T1 - Determinants of treatment response to sulfadoxine-pyrimethamine and subsequent transmission potential in falciparum malaria
AU - Méndez, Fabián
AU - Muñoz, Álvaro
AU - Carrasquilla, Gabriel
AU - Jurado, Diana
AU - Arévalo-Herrera, Myriam
AU - Cortese, Joseph F.
AU - Plowe, Christopher V.
N1 - Funding Information:
Supported in part by the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (ID–990223), by the STATEPI Group of the Johns Hopkins Bloomberg School of Public Health, by the Fundacion para la Educacion Superior, by the Valle State Secretary of Health in Colombia, and by US National Institute of Allergy and Infectious Diseases grant R01-AI-44824.
PY - 2002/8/1
Y1 - 2002/8/1
N2 - Drug resistance is contributing to increasing mortality from malaria worldwide. For assessment of the role of resistance-conferring parasite mutations on treatment responses to sulfadoxine-pyrimethamine (SP) and transmission potential, 120 subjects with uncomplicated falciparum malaria from Buenaventura, Colombia, were treated with SP and followed for 21 days in the period February 1999 to May 2000. Exposures of interest were mutations in Plasmodium falciparum dihydrofolate reductase (DHFR) and dihydropteroate synthase that confer resistance to pyrimethamine and sulfadoxine, respectively. Although SP was highly efficacious (96.7%), the presence together of DHFR mutations at codons 108 and 51 was associated with longer parasite clearance time (relative hazard = 0.24, p = 0.019) more so than the 108 mutation alone (relative hazard = 0.45, p = 0.188). This association remained after controlling for potential confounders. Infections with these mutations were also associated with the presence of gametocytes, the sexual form of the parasite responsible for transmission, 14 and 21 days after treatment (p = 0.016 and p = 0.048, respectively). Higher gametocytemia is probably due to DHFR mutations prolonging parasite survival under drug pressure, resulting in longer parasite clearance time and allowing asexual parasites to differentiate into gametocytes. These results suggest that even when SP efficacy is high, DHFR mutations that are insufficient to cause therapeutic failure may nevertheless increase malaria transmission and promote the spread of drug resistance.
AB - Drug resistance is contributing to increasing mortality from malaria worldwide. For assessment of the role of resistance-conferring parasite mutations on treatment responses to sulfadoxine-pyrimethamine (SP) and transmission potential, 120 subjects with uncomplicated falciparum malaria from Buenaventura, Colombia, were treated with SP and followed for 21 days in the period February 1999 to May 2000. Exposures of interest were mutations in Plasmodium falciparum dihydrofolate reductase (DHFR) and dihydropteroate synthase that confer resistance to pyrimethamine and sulfadoxine, respectively. Although SP was highly efficacious (96.7%), the presence together of DHFR mutations at codons 108 and 51 was associated with longer parasite clearance time (relative hazard = 0.24, p = 0.019) more so than the 108 mutation alone (relative hazard = 0.45, p = 0.188). This association remained after controlling for potential confounders. Infections with these mutations were also associated with the presence of gametocytes, the sexual form of the parasite responsible for transmission, 14 and 21 days after treatment (p = 0.016 and p = 0.048, respectively). Higher gametocytemia is probably due to DHFR mutations prolonging parasite survival under drug pressure, resulting in longer parasite clearance time and allowing asexual parasites to differentiate into gametocytes. These results suggest that even when SP efficacy is high, DHFR mutations that are insufficient to cause therapeutic failure may nevertheless increase malaria transmission and promote the spread of drug resistance.
KW - Dihydropteroate synthase
KW - Drug resistance
KW - Malaria
KW - Plasmodium falciparum
KW - Pyrimethamine
KW - Sulfadoxine
UR - http://www.scopus.com/inward/record.url?scp=0036681854&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036681854&partnerID=8YFLogxK
U2 - 10.1093/aje/kwf030
DO - 10.1093/aje/kwf030
M3 - Article
C2 - 12142257
AN - SCOPUS:0036681854
VL - 156
SP - 230
EP - 238
JO - American Journal of Epidemiology
JF - American Journal of Epidemiology
SN - 0002-9262
IS - 3
ER -